The field of the invention is immune suppression.
An effective immune response begins when an antigen or mitogen triggers the activation of T cells. In the process of T cell activation, numerous cellular changes occur, which include the expression of cytokines and cytokine receptors. One of the cytokines involved in the immune response is interleukin-15 (IL-15), which is a T cell growth factor that stimulates the proliferation and differentiation of B cells, T cells, natural killer (NK) cells, and lymphocyte-activated killer (LAK) cells in vitro. In vivo, the proliferation of these cell types enhances the immune response.
Patients benefit from suppression of the immune response in a number of circumstances, for example, in the event of organ transplantation or immune disease, particularly autoimmune disease. In other circumstances, for example when select immune cells have become malignant or autoaggressive, it is beneficial to actively destroy them.
The present invention is based on the discovery of novel ways to suppress the immune response. In each case, suppression is achieved by administration of a first agent that targets an interleukin-15 receptor (IL-15R) and a second agent that blocks a costimulatory signal that is normally transmitted from antigen presenting cells (APCs) to T cells. Accordingly, the invention features methods of treating a patient who would benefit from immune suppression (e.g., a patient who has received, or is scheduled to receive, a transplant or who has an immune disease, particularly an autoimmune disease) by administering one or more agents that target an IL-15R and one or more agents that block a costimulatory signal. The invention also features therapeutic compositions that include one or more of each of the first and second agents described above. Although such compositions would necessarily contain more than one agent, the methods of the invention are not limited to those in which the agents are necessarily administered simultaneously. The agents of the invention, and methods for their use, are described below.
Many of the agents used in the context of the present invention have advantageous therapeutic characteristics. For example, agents that target an IL-15R can be fusion proteins that include a mutant IL-15 (mIL-15) polypeptide. These agents are unlikely to be immunogenic because the mutant IL-15 portion of the fusion protein can differ from wild type IL-15 by only a few substituted residues. In addition, since mIL-15 polypeptides can bind the IL-15Rxcex1 with the same high affinity as wild type IL-15, they can compete effectively for the receptor. Further, agents of the invention can activate components of the host immune system, such as complement and phagocytes, that ultimately mediate an elimination, i.e. depletion, of cells bearing the receptor to which the agent binds (by, e.g., mediating lysis or phagocytosis of targeted cells). As the alpha subunit of the IL-15 receptor (IL-15Rxcex1) is expressed by activated or malignant immune cells, but not by resting immune cells, agents of the invention can be used to specifically target those cells that have been activated (e.g., antigen-activated T cells) or that have become malignant. A further advantage of the invention is that when an agent that targets an IL-15R is administered with an agent that blocks a costimulatory signal, tolerance is induced. Consequently, immunosuppression can be discontinued without the graft being rejected or secondary grafts can be accepted without further immunosuppression.
Other features and advantages of the invention will be apparent from the following detailed description and from the claims. Although materials and methods similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred materials and methods are described below.